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May 23, 2014 - 1. Introduction. Paragangliomas (PGLs) are rare neuroendocrine tumors that arise in sympathetic and parasympathetic paraganglia and derive.

International Journal of Surgery 12 (2014) S63eS67

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Resection of Carotid Body Tumors reduces arterial blood pressure. An underestimated neuroendocrine syndrome Stefano de Franciscis a, b, Raffaele Grande b, Lucia Butrico b, Gianluca Buffone a,  e, Domenico De Vito h, Luca Gallelli c, Edoardo Scarcello d, Francesco Giuseppe Calio a, h h f , Maurizio Amato , Francesco Fugetto , Vincenzo Gasbarro a, g, Rita Compagna a, h , Raffaele Serra a, b, * Bruno Amato a

Interuniversity Center of Phlebolymphology (CIFL), International Research and Educational Program in Clinical and Experimental Biotechnology, Headquarters: University Magna Graecia of Catanzaro, Viale Europa, 88100 Catanzaro, Italy b Department of Medical and Surgical Sciences, University of Catanzaro, Italy c Department of Health Science, University of Catanzaro, Italy d Unit of Vascular Surgery, Annunziata Hospital, Cosenza, Italy e Unit of Vascular Surgery, S. Anna Hospital, Catanzaro, Italy f University of Modena and Reggio Emilia, Corso Canal Grande, 41011 Modena, Italy g Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy h Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Italy

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 March 2014 Accepted 3 May 2014 Available online 23 May 2014

Introduction: Carotid Body Tumors (CBTs) are Paragangliomas (PGLs) located in the head and neck region which usually do not cause overt neuroendocrine symptoms and hypertension. Matrix Metalloproteinases (MMPs) have shown a strong correlation between CBTs and their clinical behavior. Aim of this study is to analyze the relationship between changes in arterial blood pressure and metalloproteinases levels after surgical resection of CBTs. Methods: We performed a multicenter clinical study on 17 patients with benign and malignant CBTs (5 males; 12 females). Tumors were completely resected and biopsies, obtained at the time of surgery, were lysed for Western blot analysis to determine MMPs levels in tissues. An enzyme-linked immune sorbent assay (ELISA) kit was used to determine the concentration of MMPs in plasma fluid. Blood pressure values were measured at admission and at 10 days after surgery. Results: At the time of the admission, blood pressure values were higher in patients with CBTs respect to control patients; moreover in patients with malignant CBTs blood pressure values were higher (P < 0.01) respect to patients with benign CBTs. 10 days after the surgery, we documented a significant decrease (P < 0.01) in blood pressure values and in MMPs levels in all patients with CBTs. Conclusion: These results suggest that, despite the CTBs are considered non-functional tumors, an “underestimated” neuroendocrine activity on arterial blood pressure may be detected. © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Keywords: Carotid Body Tumor Surgery Arterial blood pressure Neuroendocrine syndrome Metalloproteinases

1. Introduction Paragangliomas (PGLs) are rare neuroendocrine tumors that arise in sympathetic and parasympathetic paraganglia and derive from neural crest cells. In 80e85% of cases, PLGs are

* Corresponding author. Department of Medical and Surgical Science, University  Germaneto, 88100 Catanzaro, Magna Graecia of Catanzaro, Viale Europa, Localita Italy. E-mail address: [email protected] (R. Serra). http://dx.doi.org/10.1016/j.ijsu.2014.05.052 1743-9191/© 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

pheochromocytomas (PCCs), whereas 15e20% are located in extraadrenal chromaffin tissue [1]: Carotid Body Tumors (CBTs) are the most common paraganglioma (PLG) in the head and neck [2]. Usually, PGLs are benign lesions and the development of metastasis is uncommon (approximately 6%) [3,4]. CBTs have an incidence of about 1 in 30,000 [2] and are mostly benign neoplasms of the middle age [5] with a 5% of metastatic rate [6e8]. These tumors are often identified accidentally as a painless slow-growing mass and diagnosis is delayed because of subtle symptoms. Several studies have shown that hypertension, the main

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sign of neuroendocrine syndrome, is a common feature of PGLs and it can be continuous, intermittent, and often paroxysmal in nature with associated typical signs, such us palpitations, headache and diaphoresis [9e12]; nevertheless, benign as well as malignant PLGs located in the head and neck region, such us CBTs, usually do not cause neuroendocrine symptoms and/or hypertension [13e17]. These tumors causes progressive symptoms such as dysphagia, odynophagia, hoarseness of voice or cranial nerve deficits because of the strong proximity to the neck vascular, nervous and muscular structures [2,18,19]. Matrix metalloproteinases (MMPs)are zincdependent endopeptidases which degrade various components of the extracellular matrix (ECM) and release growth factors and cytokines that reside in the ECM [20]; ECM remodeling is regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Through their enzymatic activity, MMPs play several roles in tumor invasion and metastasis [21] and are involved in the pathogenesis of major inflammatory [22] and vascular diseases [23e33]. Our recent experience has shown a strong correlation between PLGs (both benign and malignant neoplasms) and the expression of MMPs [34] as well as recent studies have suggested that altered expression and activity of MMPs, particularly MMP-1, -2, -3, -9, may be implicated in vascular remodeling of several cardiovascular diseases [35e38]. In this study in patients with benign and malignant CBTs we evaluated the levels of MMP-1, -2, -3, -9 in plasma and we correlated these with the values of blood pressure at admission and after surgical excision of the tumor.

linked immune sorbent assay (ELISA) kit was used to determine the concentration of MMPs in plasma fluid. A commercially available sandwich ELISA kit with an MMPs monoclonal antibody was used to determine plasma MMP-s levels. According to recent classification [39], in all patients the valuation of blood pressure before surgical excision and 10 days later was performed (Table 2). A further group of healthy volunteer patients (Group II) of both sexes were enrolled and represented the control group. As previously described [34], in these patients we take the blood samples in order to evaluate through the ELISA test the MMPs values and we also evaluated the blood pressure values. For both Groups I and II medical history was recorded, and clinical examination, laboratory findings, duplex ultrasonography were performed. 2.3. Statistical analysis All data are expressed as mean ± standard error medium (SEM). Student's t test was performed in order to analyze the difference between each group with their control. Anova test was used to evaluate the difference between the groups. Differences identified by ANOVA were pinpointed by unpaired Student's t test. The test of Pearson was used to evaluate the correlation between plasma MMPs levels and blood pressure values. The threshold of statistical significance was set at *P < 0.05. SPSS (SPSS Inc., Chicago, USA) software was used for statistical analyses. We defined this study as exploratory, therefore we did not determine a power calculation. In this light, these results could only be labeled as exploratory.

2. Materials and methods 3. Results 2.1. Study population and experimental protocol We performed a multicenter clinical study, conducted between January 2013 and December 2013 (1-year-period) with prior approval from the Institutional Review Board at the University of Catanzaro, in accordance with the Declaration of Helsinki and the Guideline for Good Clinical Practice. Patients were enrolled in Department of Medical and Surgical Science of University “Magna Graecia” of Catanzaro, Department of General, Geriatric, Oncologic Surgery and Advanced Technologies of University of Naples “Federico II”, Unit of Vascular and Endovascular Surgery, Department of Surgical, Anesthesiological and Radiological Sciences, University of Ferrara, Sant'Anna Hospital of Catanzaro and Unit of Vascular and Endovascular Surgery, Annunziata Hospital, Cosenza. Before the beginning of the study, all participants provided a written informed consent. The patients with diagnosis of CBTs were enrolled at the time of our previous study [34]. 2.2. Experimental protocol We performed a retrospective analysis of data from medical records of 14 previously enrolled patients with CBTs [34]. Moreover, we performed also a prospective study in patients enrolled in 2013. As previously described [34], patients eligible for the study were of both sexes, from 20 up to 70 years, with diagnosis of benign and malignant vascular tumors. Tumors were completely resected according to the recent surgical technique and anatomo-pathological examination of operative sample was performed. Biopsies obtained at the time of surgery were lysed for Western blot analysis in agreement with our previous studies [13e14,17,19], anti-MMPs monoclonal antibodies were used and results were expressed as arbitrary units in agreement with our previous papers [23,25,26,29,31]. All experiments were performed in triplicate. In agreement with our previous papers [23,25,26,29,31], an enzyme-

In the present multicenter study we enrolled 3 patients (1 male and 2 females) with carotid benign paraganglioma, while data from 14 patients (4 males and 10 females; 11 patients with benign paraganglioma and 3 patients with malignant one) enrolled in a previous study were analyzed. Moreover, 3 health patients were enrolled in control group (1 male and 2 females). At the time of the admission, blood pressure values were higher in patients with CBTs respect to control patients (data not shown); moreover in patients with malignant CBTs (numbers 15e17) blood pressure values were higher (P < 0.01) respect to patients with benign CBTs (numbers 1e14). ELISA findings performed on blood samples take at the time of admission, revealed significantly higher levels (P < 0.01) of MMP-1, MMP-2, MMP-3, MMP-8 and MMP-9 in patients with paraganglioma respect to control patients (data not shown). Moreover, patients with malignant CBTs (patient numbers 15e17) showed significantly higher levels (P < 0.01) of MMP-1, MMP-2 and MMP-3, respect to patients with benign CBTs (patient numbers 1e14) (Table 1). No significant differences were documented in plasma values of MMP-7 and MMP-13 between patients with malignant (numbers 15e17) and patients with benign ones (patient numbers 1e14) (Table 1). An increased expression (P < 0.01) of MMP-1, MMP-2 and MMP3, but not in MMP-7, MMP-8 and MMP-9, were recorded through western blot in patients with malignant paraganglioma respect to patients with benign one (data not shown). Finally, blood pressure evaluation and Elisa test performed 10 days after the surgery, documented a significant decrease (P < 0.01) in blood pressure values and in MMPs levels, without differences between patients with malignant CBTs (numbers 15e17) and patients with benign one (numbers 1e14) (Table 2). Finally using Pearson's test we documented a significant correlation (P < 0.01) between blood pressure (systolic, diastolic and differential) and MMPs, particularly with MMP1.

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Table 1 Blood pressure values (mmHg) and plasma matrix metalloproteinases levels (ng/mL) at the time of admission in patients with benign (numbers 1e14) and with malignant CBTs (number 15e17). Patients

PAS

PAD

DBP

MMP1

MMP2

MMP3

MMP7

MMP8

MMP9

MMP13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

130 134 132 130 130 138 134 132 130 136 135 130 134 132 158 162 154

86 88 88 86 84 89 86 88 86 89 87 87 88 86 98 102 94

44 46 44 44 46 49 48 44 44 49 48 43 46 46 60 60 60

3.7 3.9 4.1 3.4 3.6 3.8 3.2 3.9 4.1 3.6 3.8 3.7 3.8 3.7 4.7 5.1 5.3

690 695 688 702 711 695 693 702 708 713 697 689 710 695 916 927 911

9.1 8.7 8.9 9.5 9.1 9.8 8.2 9.2 9 9.5 9.1 9.21 9.05 9.16 16.9 17.3 16.5

0.38 0.4 0.39 0.37 0.35 0.49 0.37 0.39 0.37 0.48 0.42 0.35 0.39 0.38 0.9 0.94 0.91

15 15.2 15.4 15.1 15.1 15.8 15.5 15.3 14.9 15.9 15.3 15.7 16 14.9 16.2 15.9 16.3

88 92 92 89 91 99 94 92 90 95 93 87 89 90 89 93 94

0.86 0.84 0.83 0.88 0.87 0.88 0.85 0.83 0.81 0.82 0.87 0.84 0.86 0.88 0.91 0.92 0.88

BPS: systolic blood pressure; BPD: diastolic blood pressure; DBP: differential blood pressure; MMP: matrix metalloproteinases.

4. Discussion Carotid body is a physiologically important paraganglion that responds to hypoxia by detecting the hydrogen ion concentration and feeding back to the respiratory center in the brainstem: it sends impulses to the external intercostal muscles, diaphragm, vasculature, and heart, thus reflexively increasing the rate and depth of ventilation, as well as slightly increasing blood pressure and heart rate [40]. CBT often present as slow growing, nontender neck masses located just anterior to the sternocleidomastoid muscle at the level of the hyoid. As previously described [2], tumor is mobile in the lateral plane but its mobility is limited in the cephalo-caudal direction [41], tumor mass may transmit the carotid pulse or demonstrate a bruit or thrill [42] and may causes compression and infiltration of cranial nerves (VIIeIXeXXIeXII). CBTs are usually classified using the criteria described by Shamblin and co-workers [2,43]. These tumors are mainly nonfunctional; some CBTs may be functional and convey catecholamine, such as norepinephrine, epinephrine, dopamine, and serotonin, or trigger catecholamine-induced signs and symptoms which can produce cardiovascular and metabolic symptoms such as palpitations, hypertension, stroke, shortness of breath and weight loss [44e49]. Evidence of increased

endocrine activity demonstrates only1e3% of CBTs [50] and high blood pressure is the common feature. Our study showed interesting data:  all enrolled patients showed a significant reduction of blood pressure after the surgical excision of the tumor, especially those who had, at admission, high blood pressure according to recent classifications [39];  MMP-1, -2, -3, -9 were the protease mostly expressed in CBTs and, at the same time, those which, according to literature [35e38], have been involved in the pathophysiological processes that hypertension induces on vessels;  at admission, MMP-1, -2, -3, -9 concentration were higher in patients with higher blood pressure;  evaluation of MMP-1, -2, -3, -9 concentration after surgery showed an evident reduction of their levels;  reduction of MMPs concentration within 7e10 days (after surgery) was consensual and parallel with the reduction of blood pressure (P < 0.005). These results suggest that, despite the CTBs of our study are of non-functional tumors, an “underestimated” neuroendocrine activity was detected.

Table 2 Blood pressure values (mmHg) and plasma matrix metalloproteinases levels (ng/mL) 10 days after the surgery in patients with benign (numbers 1e14) and with malignant CBTs (number 15e17). Patients

PAS

PAD

DBP

MMP1

MMP2

MMP3

MMP7

MMP8

MMP9

MMP13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

126 128 126 124 122 128 126 130 128 126 122 128 130 124 129 132 130

82 84 84 81 83 88 84 82 80 82 85 83 84 82 88 89 83

44 44 42 43 39 40 42 48 48 44 37 45 46 42 41 43 47

2.88 2.58 2.62 2.63 2.55 2.9 2.75 2.76 2.85 2.86 2.83 2.86 2.62 2.69 2.66 2.62 2.88

483 488 485 478 480 487 486 482 481 493 485 486 488 487.55 480.68 483.23 490.21

7.2 7.4 7.2 6.9 7.1 7.7 7.4 7.2 7 7.65 7.5 7.3 7.4 7.2 7.3 7.28 7.65

0.35 0.37 0.33 0.32 0.31 0.38 0.36 0.33 0.31 0.38 0.36 0.351 0.375 0.332 0.324 0.315 0.378

8.8 9.2 9.4 8.7 8.9 9.8 9.4 9.1 8.89 9.8 9.5 8.85 9.3 9.48 8.75 9.2 8.45

88 94 92 90 87 95 94 92 89 98 95 94.7 91.5 92.2 93.5 93.65 95.8

0.78 0.804 0.803 0.77 0.82 0.815 0.816 0.81 0.789 0.8 0.82 0.787 0.798 0.806 0.787 0.812 0.803

BPS: systolic blood pressure; BPD: diastolic blood pressure; DBP: differential blood pressure; MMP: matrix metalloproteinases.

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Ethical approval IRB approval by IRB/IEC of Interuniversity Center of Phlebolymphology (CIFL). International Research and Educational Program in Clinical and Experimental Biotechnology e at University Magna Graecia of Catanzaro was obtained. Reference number: ER.ALL.2013.28.A. Author contribution SdF: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data; also participated substantially in the drafting and editing of the manuscript. RG: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data; also participated substantially in the drafting and editing of the manuscript. LB: Participated substantially in data collection, and execution of the study and in the analysis and interpretation of data. GB: Participated substantially in data collection, and execution of the study and in the analysis and interpretation of data. LG: Participated substantially in data collection and execution of the study and in the analysis and interpretation of data; also participated substantially in the drafting and editing of the manuscript. ES: Participated substantially in data collection and execution of the study and in the analysis and interpretation of data. FGC: Participated substantially in data collection, and execution of the study and in the analysis and interpretation of data. FG: Participated substantially in data collection and execution of the study and in the analysis and interpretation of data. DDV: Participated substantially in data collection and execution of the study and in the analysis and interpretation of data. RC: Partecipated substantially in data collection and execution of the study and in the analysis and interpretation of data. MA: Participated substantially in data collection and execution of the study and in the analysis and interpretation of data. VG: Participated substantially in data collection and execution of the study and in the analysis and interpretation of data. BA: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data; also participated substantially in the drafting and editing of the manuscript. RS: Partecipated substantially in conception, design, and execution of the study and in the analysis and interpretation of data; also participated substantially in the drafting and editing of the manuscript. Funding All authors have no source of funding. Conflicts of interest All authors have no conflict of interests. Acknowledgment This work received no funding. The authors declare that they have no competing interests. References [1] K.E. Joynt, J.J. Moslehi, K.L. Baughman, Paragangliomas: etiology, presentation, and management, Cardiol. Rev. 17 (4) (2009) 159e164.

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